Biodegradable phosphoester polyamines

ABSTRACT

Novel biodegradable phosphoester polyamines are disclosed. The biodegradable phosphoester polyamines may be utilized as cross-linkers for sprayable compositions which may be used as tissue adhesives or sealants.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National State Application of PCT/US2007/004477under 35USC §371 (a), which claims priority of U.S. Provisional PatentApplication Ser. No. 60/775,749 filed Feb. 22, 2006, the disclosures ofeach of the above-identified applications are hereby incorporated byreference in their entirety.

BACKGROUND

1. Technical Field

The present disclosure relates to biodegradable phosphoester polyaminesand their use in the formation of compositions, such as adhesives ortissue sealants.

2. Background of Related Art

In recent years there has developed increased interest in replacing oraugmenting sutures with adhesive bonds. The reasons for this increasedinterest include: (1) the potential speed with which repair might beaccomplished; (2) the ability of a bonding substance to effect completeclosure, thus preventing seepage of fluids; and (3) the possibility offorming a bond without excessive deformation of tissue.

For surgical adhesives to be accepted by surgeons, they should exhibithigh initial tack and an ability to bond rapidly to living tissue; thestrength of the bond should be sufficiently high to cause tissue failurebefore bond failure; the adhesive should form a bridge, typically apermeable flexible bridge; and the adhesive bridge and/or its metabolicproducts should not cause local histotoxic or carcinogenic effects.

Several materials useful as tissue adhesives or tissue sealants arecurrently available. One type of adhesive that is currently available isa cyanoacrylate adhesive. However, cyanoacrylate adhesives can have ahigh flexural modulus which can limit their usefulness. Another type oftissue sealant that is currently available utilizes components derivedfrom bovine and/or human sources. For example, fibrin sealants areavailable. However, as with any natural material, variability in thematerial can be observed. It would be desirable to provide a fullysynthetic biological adhesive or sealant.

SUMMARY

The present disclosure provides biodegradable phosphoester polyamines.The biodegradable phosphoester polyamines include, in embodiments,polyamine functionalized phosphoester-ester-ether oligomers andpolymers. These biocompatible compositions may be utilized ascross-linkers for sprayable compositions. The sprayable compositionsinclude, in embodiments, tissue adhesives and sealants, includingmultiisocyanate-polyether-polyurethane sealants.

In embodiments, the present disclosure provides a biocompatiblecomposition including a biodegradable phosphoester polyamine of thefollowing formula:

wherein R¹ is selected from the group consisting of polyethers,polyesters, poly(ether-ester) blocks and combinations thereof, R² is ahydrogen atom, a protecting group or an organic moiety having from about1 to about 50 carbon atoms, and NH—R³—NH₂ is derived from a polyamineselected from the group consisting of ethylene diamine, hexamethylenediamine, lysine, N-(3-aminopropyl)-1,4-butanediamine,N,N′-bis(3-aminopropyl)-1,4-butanediamine, isomers of hexamethylenediamine, diethylene triamine, triethylene tetramine, tetraethylenepentamine, bishexamethylene triamine, N,N′-bis(3-aminopropyl)-1,2-ethanediamine, N-(3-Aminopropyl)-1,3-propane diamine, N-(2-aminoethyl)-1,3propane diamine, cyclohexane diamine, isomers of cyclohexane diamine,4,4′-methylene biscyclohexane amine, 4′4′-methylenebis(2-methylcyclohexanamine), toluene diamine, phenylene diamine,isophorone diamine, phenalkylene polyamines, amino-functionalizedpolyalkylene oxides, polypeptides, and combinations thereof.

In other embodiments, the present disclosure provides compositionsincluding an isocyanate prepolymer and a biodegradable phosphoesterpolyamine of the following formula:

wherein R¹ is selected from the group consisting of polyethers,polyesters, poly(ether-ester) blocks and combinations thereof, R² is ahydrogen atom, a protecting group or an organic moiety having from about1 to about 50 carbon atoms, and NH—R³—NH₂ is derived from a polyamineselected from the group consisting of ethylene diamine, hexamethylenediamine, lysine, N-(3-aminopropyl)-1,4-butanediamine,N,N′-bis(3-aminopropyl)-1,4-butanediamine, isomers of hexamethylenediamine, diethylene triamine, triethylene tetramine, tetraethylenepentamine, bishexamethylene triamine, N,N′-bis(3-aminopropyl)-1,2-ethanediamine, N-(3-Aminopropyl)-1,3-propane diamine, N-(2-aminoethyl)-1,3propane diamine, cyclohexane diamine, isomers of cyclohexane diamine,4,4′-methylene biscyclohexane amine, 4′4′-methylenebis(2-methylcyclohexanamine), toluene diamine, phenylene diamine,isophorone diamine, phenalkylene polyamines, amino-functionalizedpolyalkylene oxides, polypeptides, and combinations thereof, wherein thebiodegradable phosphoester polyamine crosslinks the isocyanateprepolymer.

In other embodiments, the present disclosure provides processesincluding combining a hydroxyl-terminated component with a phosphoesterto form a phosphoester functionalized compound, and combining thephosphoester functionalized compound with a polyamine to produce abiodegradable phosphoester polyamine.

DETAILED DESCRIPTION

The present disclosure relates to novel biodegradable phosphoesterpolyamines. The phosphoester polyamines are biocompatible,non-immunogenic and biodegradable. In embodiments, the biodegradablephosphoester polyamines may be utilized as cross-linkers for tissueadhesives and sealants, including multiisocyanate-polyether-polyurethanesealants. Such sealants may be employed to adhere tissue edges, sealair/fluid leaks in tissues, adhere medical devices, i.e. implants, totissue, and for tissue augmentation such as sealing or filling voids ordefects in tissue. The compositions can be applied to living tissueand/or flesh of animals, including humans.

The biodegradable phosphoester polyamines of the present disclosure mayinclude polyamine functionalized phosphoester-ester-ether oligomers andpolymers. In embodiments, the biodegradable phosphoester polyamine maybe generated by endcapping a hydroxyl-terminated component with aphosphoester, optionally in the presence of an amine such as a tertiaryamine. The phosphoester group may then be end-capped with a polyaminehaving at least one primary/secondary amino group. Methods for reactingpolyamines with phosphoester groups are within the purview of thoseskilled in the art and include, for example, the methods disclosed inDewa et al., “Novel Polyamine-Dialkyl Phosphate Conjugates for GeneCarriers. Facile Synthetic Route via an Unprecedented DialkylPhosphate.” Bioconjugate Chem. 2004, 15, pp. 824-830, the entiredisclosure of which is incorporated by reference herein.

Suitable hydroxyl-terminated components include, for example,hydroxyl-terminated polyethers, polyesters, and/or poly(ether-ester)blocks. Suitable polyethers which may be utilized are within the purviewof those skilled in the art and include, for example, polymers andcopolymers of polyethylene glycol, polypropylene glycol, polybutyleneglycol, polytetramethylene glycol, polyhexamethylene glycol, andcombinations thereof. Suitable polyesters which may be utilized arewithin the purview of those skilled in the art and include, for example,polymers and copolymers of trimethylene carbonate, ε-caprolactone,p-dioxanone, glycolide, lactide, 1,5-dioxepan-2-one, polybutyleneadipate, polyethylene adipate, polyethylene terephthalate, andcombinations thereof. Suitable poly(ether-ester) blocks are within thepurview of one skilled in the art and include, but are not limited to,polyethylene glycol-polycaprolactone, polyethylene glycol-polylactide,polyethylene glycol-polyglycolide and various combinations of theindividual polyethers and polyesters described herein. Additionalexamples of poly(ether-ester) blocks are disclosed in U.S. Pat. No.5,578,662 and U.S. Patent Application No. 2003/0135238, the entirecontents of each of which are incorporated by reference herein.

In embodiments, the hydroxyl-terminated precursor components can bepolyethylene glycol, methoxy polyethylene glycol, glycolide-polyethyleneglycol-caprolactone copolymers, aliphatic oligoesters, combinationsthereof, and the like.

Suitable phosphoesters which may be utilized to endcap thehydroxyl-terminated precursor components include, but are not limitedto, dichloro-phosphoesters such as ethyl dichlorophosphate (EOP). Inembodiments, the hydroxyl-terminated precursor may be combined with thephosphoester in an organic solvent such as tetrahydrofuran (THF),dimethylformamide (DMF), dichloromethane (CH₂Cl₂), combinations thereof,and the like. In other embodiments, the phosphoester may be combinedwith the hydroxyl-terminated precursor in the presence of an amine suchas a tertiary amine. Suitable tertiary amines which may be utilizedinclude, for example, triethylamine, dimethylaminopropylamine, pyridine,dimethylaniline, N,N-dimethylaniline, N-ethylpiperidine,N-methylpyrrolidine, N,N,N′,N′-tetramethylethylenediamine,N,N,N′,N′-tetramethylethylenediamine, 1,2-dipiperidinoethane,trimethylaminoethylpiperazine, N,N,N′,N″,N″-pentamethylethylenetriamine,N,N′-dioctyl-p-phenylenediamine, combinations thereof, and the like.

In embodiments, the reaction scheme for functionalizing thehydroxyl-terminated precursor component with a phosphoester may includethe following:

wherein R¹ may be a polyether, polyester, and/or poly(ether-ester) blockas described above, or combinations thereof, and R² may be a hydrogenatom, a protecting group or an organic moiety containing from about 1 toabout 50 carbon atoms, in embodiments from about 2 to about 20 carbonatoms.

The phosphoester functionalized compound thus produced may then beendcapped with a polyamine having at least one primary or secondaryamino group. Suitable polyamines having at least one primary/secondaryamino group include, but are not limited to, ethylene diamine,hexamethylene diamine, lysine, spermidine(N-(3-aminopropyl)-1,4-butanediamine), spermine(N,N-bis(3-aminopropyl)-1,4-butanediamine), isomers of hexamethylenediamine, diethylene triamine, triethylene tetramine, tetraethylenepentamine, bishexamethylene triamine, N,N-bis(3-aminopropyl)-1,2-ethanediamine, N-(3-Aminopropyl)-1,3-propane diamine, N-(2-aminoethyl)-1,3propane diamine, cyclohexane diamine, isomers of cyclohexane diamine,4,4′-methylene biscyclohexane amine, 4′4′-methylenebis(2-methylcyclohexanamine), toluene diamine, phenylene diamine,isophorone diamine, and phenalkylene polyamines. In embodiments,combinations of the foregoing polyamines may be utilized.

In another embodiment, the polyamine may be a polyamino functionalmacromer compound, including polyoxyalkylene amines sold under the nameJEFFAMINE® by Huntsman Performance Chemicals (Houston, Tex.), otheramino-functionalized polyalkylene oxides, polypeptides includingpolypeptides having lysine and/or arginine residues, and the like. Insome embodiments, combinations of any of the foregoing polyamines may beutilized.

In embodiments, the phosphoester functionalized compound may beendcapped with the polyamine in accordance with the following reactionscheme.

wherein R¹ and R² may be as defined above and NH—R³—NH₂ may be derivedfrom the polyamine described above.

The resulting biodegradable phosphoester polyamines of the presentdisclosure may be utilized in numerous medical applications. Inembodiments, the biodegradable phosphoester polyamines of the presentdisclosure may be used as a crosslinker for a tissue adhesive orsealant. For example, the biodegradable phosphoester polyamine of thepresent disclosure may be utilized as a cross-linker for a sprayablemultiisocyanate-polyurethane sealant. In such an embodiment, thebiodegradable phosphoester polyamines of the present disclosure may becombined with a second component such as an isocyanate prepolymerrepresented by the formula:

wherein X is a polyether, a polyester or a polyether-ester group; and Ris an aromatic, aliphatic, or alicyclic group.

Suitable polyethers which may be utilized as a component of theisocyanate prepolymer are within the purview of those skilled in the artand include, for example, polyethylene glycol, polypropylene glycol,polybutylene glycol, polytetramethylene glycol, polyhexamethyleneglycol. In a particularly useful embodiment the polyether ispolyethylene glycol or a derivative thereof, such as methoxypolyethylene glycol.

Suitable polyesters which may be utilized as a component of theisocyanate prepolymer are within the purview of those skilled in the artand include, for example, trimethylene carbonate, s-caprolactone,p-dioxanone, glycolide, lactide, 1,5-dioxepan-2-one, polybutyleneadipate, polyethylene adipate, and polyethylene terephthalate.

In addition, the second component may include a poly(ether-ester) block.Any suitable poly(ether-ester) block within the purview of those skilledin the art may be utilized as a component of the isocyanate prepolymer.Some examples include, but are not limited to, polyethyleneglycol-polycaprolactone, polyethylene glycol-polylactide, polyethyleneglycol-polyglycolide and various combinations of the individualpolyethers and polyesters described herein. Additional examples ofpoly(ether-ester) blocks are disclosed in U.S. Pat. No. 5,578,662 andU.S. Patent Application No. 2003/0135238, the entire contents of each ofwhich are incorporated by reference herein.

In addition to the polyether, polyester or poly(ether-ester) block, thesecond component may be endcapped with an isocyanate to produce adiisocyanate-functional compound. Suitable isocyanates for endcappingthe aliphatic polyether, polyester or poly(ether-ester) block includearomatic, aliphatic and alicyclic isocyanates. Examples include, but arenot limited to, aromatic diisocyanates such as 2,4-toluene diisocyanate,2,6-toluene diisocyanate, 2,2′-diphenylmethane diisocyanate,2,4′-diphenylmethane diisocyanate, 4,4′-diphenylmethane diisocyanate,diphenyldimethylmethane diisocyanate, dibenzyl diisocyanate, naphthylenediisocyanate, phenylene diisocyanate, xylylene diisocyanate,4,4′-oxybis(phenylisocyanate) or tetramethylxylylene diisocyanate;aliphatic diisocyanates such as tetramethylene diisocyanate,hexamethylene diisocyanate, dimethyl diisocyanate, lysine diisocyanate,2-methylpentane-1,5-diisocyanate, 3-methylpentane-1,5-diisocyanate or2,2,4-trimethylhexamethylene diisocyanate; and alicyclic diisocyanatessuch as isophorone diisocyanate, cyclohexane diisocyanate, hydrogenatedxylylene diisocyanate, hydrogenated diphenylmethane diisocyanate,hydrogenated trimethylxylylene diisocyanate, 2,4,6-trimethyl1,3-phenylene diisocyanate or commercially available DESMODURS® fromBayer Material Science.

Methods for endcapping the polyether, polyester or poly(ether-ester)block with a diisocyanate are within the purview of those skilled in theart. In some embodiments, the polyether, polyester or poly(ether-ester)block may be combined with a suitable diisocyanate, in embodiments atoluene diisocyanate, and heated to a suitable temperature from about55° C. to about 75° C., in embodiments from about 60° C. to about 70°C., in embodiments about 65° C. In some embodiments the resultingdiisocyanate-functional compound may then be obtained by hot extractionwith petroleum ether.

The viscosity of the second component may be from about 10 cP to about500,000 cP, in embodiments from about 100 cP to about 200,000 cP,typically from about 200 cP to about 100,000 cP.

In embodiments, the second component may be mixed with a polar solvent.Suitable polar solvents which may be utilized are within the purview ofthose skilled in the art and include, for example, water, alcohols suchas ethanol, triethylene glycol, methoxy-polyethylene glycols,dimethylformamide, dimethylacetamide, gamma-butyrolactone,N-methylpyrrolidone, ketones such as methylethyl ketone, cyclohexanone,ethers such as diethyl ether, and mixtures of these and other polarsolvents.

The polar solvent may be mixed with the second component at a ratio offrom about 1:0.25 to about 1:10 w/w, in embodiments at a ratio of fromabout 1:1 to about 1:4 w/w.

The mixture of the second component and polar solvent as describedherein may result in an emulsion or a diluted solution. The viscosity ofthe resulting emulsion or solution may be below about 400 cP, inembodiments below about 200 cP. In some embodiments, the viscosity ofthe resulting emulsion or solution may be from about 5 cP to about 400cP, in other embodiments from about 25 cP to about 300 cP, in stillother embodiments from about 50 cP to about 150 cP. The decreasedviscosity improves the spraying of the emulsion or solution withoutsacrificing the adherence and physico-mechanical properties of thecomposition as an adhesive, sealant or drug delivery system.

In addition to the polar solvents described herein, it is envisionedthat the second component may also be mixed with polar drugs. As withthe polar solvent, the polar drugs may react with the second componentand produce an emulsion or solution with a reduced viscosity. The secondcomponent may be mixed with the polar drug and optionally a secondcomponent in situ to form synthetic drug delivery systems. Any suitablepolar drug within the purview of those skilled in the art may be used.

The biodegradable phosphoester polyamines of the present disclosure incombination with the optional second component described above may thusbe utilized, in embodiments, to produce biocompatible compositions ofthe present disclosure. The biocompatible compositions of the presentdisclosure may, in embodiments, be utilized as a tissue adhesive orsealant.

The biodegradable phosphoester polyamines of the present disclosure maybe mixed with the second component in any manner within the purview ofthose skilled in the art. In some embodiments, as noted above, thesecond component may be combined with a polar solvent. In otherembodiments, the biodegradable phosphoester polyamines of the presentdisclosure may be in an aqueous solution which, in turn, is combinedwith the second component optionally in combination with a polar solventas described above.

One example includes keeping an emulsion or solution including thesecond component and polar solvent separate from the biodegradablephosphoester polyamines of the present disclosure and spraying theindividual ingredients in a consecutive manner onto the same location,thereby allowing the two ingredients to mix and form a bond in situ.Another example includes keeping the emulsion or solution including thesecond component and polar solvent separate from the biodegradablephosphoester polyamines of the present disclosure and spraying the twoingredients simultaneously through the same nozzle, thereby allowing thetwo ingredients to mix while being sprayed.

The concentrations of the biodegradable phosphoester polyamines and thesecond component will vary depending upon a number of factors, includingthe types and molecular weights of the particular components used andthe desired end use application, i.e., to form a composition of thepresent disclosure for use as an adhesive or sealant.

Where the biodegradable phosphoester polyamines and the second componentare combined to produce adhesives or sealants, biologically activeagents, sometimes referred to herein as bioactive agents, may beincluded in the compositions of the present disclosure. For example,naturally occurring polymers, including proteins such as collagen andderivatives of various naturally occurring polysaccharides such asglycosaminoglycans, can be incorporated into the composition of thepresent disclosure.

When these other biologically active agents also contain functionalgroups, the groups will react with the functional groups on the firstand/or second components of the biocompatible composition of the presentdisclosure.

A variety of optional ingredients including medicinal agents may also beadded to the biocompatible compositions of the present disclosure. Aphospholipid surfactant that provides antibacterial stabilizingproperties and helps disperse other materials in the biocompatiblecomposition may be added. Additional medicinal agents includeantimicrobial agents, colorants, preservatives, or medicinal agents suchas, for example, protein and peptide preparations, antipyretic,antiphlogistic and analgesic agents, anti-inflammatory agents,vasodilators, antihypertensive and antiarrhythmic agents, hypotensiveagents, antitussive agents, antineoplastics, local anesthetics, hormonepreparations, antiasthmatic and antiallergic agents, antihistaminics,anticoagulants, antispasmodics, cerebral circulation and metabolismimprovers, antidepressant and antianxiety agents, vitamin Dpreparations, hypoglycemic agents, antiulcer agents, hypnotics,antibiotics, antifungal agents, sedative agents, bronchodilator agents,antiviral agents and dysuric agents.

Imaging agents such as iodine or barium sulfate, or fluorine, can alsobe combined with the compositions of the present disclosure to allowvisualization of the surgical area through the use of imaging equipment,including X-ray, MRI, and CAT scan.

Additionally, an enzyme may be added to the composition of the presentdisclosure to increase its rate of degradation. Suitable enzymesinclude, for example, peptide hydrolases such as elastase, cathepsin G,cathepsin E, cathepsin B, cathepsin H, cathepsin L, trypsin, pepsin,chymotrypsin, γ-glutamyltransferase (γ-GTP) and the like; sugar chainhydrolases such as phosphorylase, neuraminidase, dextranase, amylase,lysozyme, oligosaccharase and the like; oligonucleotide hydrolases suchas alkaline phosphatase, endoribonuclease, endodeoxyribonuclease and thelike. In some embodiments, where an enzyme is added, the enzyme may beincluded in a liposome or microsphere to control the rate of itsrelease, thereby controlling the rate of degradation of thebiocompatible composition of the present disclosure. Methods forincorporating enzymes into liposomes and/or microspheres are known tothose skilled in the art.

The biocompatible composition of the present disclosure can be used fora number of different human and animal medical applications including,but not limited to, wound closure (including surgical incisions andother wounds), adhesives for medical devices (including implants),sealants, and embolic agents. These compositions may be used to bindtissue together either as a replacement of, or as a supplement to,sutures, staples, tapes and/or bandages. Use of the disclosedcompositions as an adhesive can eliminate or substantially reduce thenumber of sutures normally required during current practices, andeliminate the subsequent need for removal of staples and certain typesof sutures and thus can be particularly useful for use with delicatetissues where sutures, clamps or other conventional tissue closuremechanisms may cause further tissue damage.

Additional applications include sealing tissues to prevent or controlblood, or other fluid leaks, at suture or staple lines. In anotherembodiment, the biocompatible composition can be used to attach skingrafts and position tissue flaps during reconstructive surgery. In stillanother embodiment, the adhesive can be used to close tissue flaps inperiodontal surgery.

To effectuate the joining of two tissue edges, the two edges areapproximated, and the composition of the present disclosure is applied,in embodiments, by spraying. The biodegradable phosphoester polyaminesand the second component crosslink rapidly, generally taking less thanone minute. The composition of the present disclosure can be used as anadhesive to close a wound, including a surgical incision. In such acase, the composition of the present disclosure can be applied to thewound and allowed to set, thereby closing the wound.

While certain distinctions may be drawn between the usage of the terms“flesh” and “tissue” within the scientific community, the terms are usedinterchangeably herein as referring to a general substrate upon whichthose skilled in the art would understand the present adhesive to beutilized within the medical field for the treatment of patients. As usedherein, “tissue” may include, but is not limited to, skin, bone, neuron,axon, cartilage, blood vessel, cornea, muscle, fascia, brain, prostate,breast, endometrium, lung, pancreas, small intestine, blood, liver,testes, ovaries, cervix, colon, stomach, esophagus, spleen, lymph node,bone marrow, kidney, peripheral blood, embryonic or ascite tissue.

In another embodiment, the present disclosure is directed to a methodfor using the biocompatible composition of the present disclosure toadhere a medical device to tissue, rather than secure two edges oftissue. In some embodiments, depending on the composition of the medicaldevice, a coating may be required on the medical device. In some casessuch a coating can include the biodegradable phosphoester polyamines orthe second component of the composition of the present disclosure. Insome aspects, the medical device includes an implant. Other medicaldevices include, but are not limited to, pacemakers, stents, shunts andthe like. Generally, for adhering a device to the surface of animaltissue, the composition of the present disclosure can be applied to thedevice, the tissue surface or both. The device, biocompatiblecomposition and tissue surface are then brought into contact with eachother and the composition is allowed to set, thereby adhering the deviceand surface to each other.

The compositions of the present disclosure can also be used to preventpost surgical adhesions. In such an application, the biocompatiblecomposition is applied and cured as a layer on surfaces of internaltissues in order to prevent the formation of adhesions at a surgicalsite during the healing process.

In addition to the formation of adhesion barriers, in embodiments thebiocompatible compositions may be utilized to form implants such asgaskets, buttresses, or pledgets for implantation.

When used as a sealant, the composition of the present disclosure can beused in surgery to prevent or inhibit bleeding or fluid leakage bothduring and after surgical procedure. It can also be applied to preventair leaks associated with pulmonary surgery. The sealant may be applieddirectly to the desired area in at least an amount necessary to seal offany defect in the tissue and seal off any fluid or air movement.

The present biocompatible composition has a number of advantageousproperties. The resulting biocompatible compositions of the presentdisclosure are safe and biocompatible, possess enhanced adherence totissue, are biodegradable, have hemostatic potential, have low cost, andare easy to prepare and use. By incorporating phosphoester andoptionally ester bonds in the biodegradable phosphoester polyamines ofthe present disclosure, the adhesive or sealant composition of thepresent disclosure prepared from the biodegradable phosphoesterpolyamine and second component described herein may be more susceptibleto non-specific hydrolysis, faster degradation, and faster mass loss,without any negative effects to the mechanical performance of theadhesive or sealant upon initial application in situ.

The following Examples are being submitted to illustrate embodiments ofthe present disclosure. These Examples are intended to be illustrativeonly and are not intended to limit the scope of the present disclosure.Also, parts and percentages are by weight unless otherwise indicated.

Example 1

A biodegradable phosphoester polyamine was synthesized byfunctionalizing a methoxy polyethylene glycol with a phosphoester, andthen endcapping the phosphoester with a polyamine.

A methoxy polyethylene glycol having a molecular weight of about 1900(mPEG) was combined with ethyl dichlorophosphate (EOP) in the presenceof triethylamine (NEt₃) and dimethylaminopyridine (DMAP) to form aphosphoester terminated methoxy polyethylene glycol. The mPEG, NEt₃, andDMAP were combined in a flask containing dichloromethane (250 mL). Theflask was placed in an ice bath, so the reaction took place at atemperature of about 0-3° C. A solution containing EOP anddichloromethane was then added dropwise to flask for about 2.5 hours.The crude mixture was placed in a refrigerator and stored overnight forabout 19 hours. The compounds utilized in the synthesis are set forthbelow in Table 1:

TABLE 1 Compound MW Mols Weight(g) Mol Ratio mPEG 1900 1900 0.01 19 1(Alfa Aesar, Lot # B12L29 (m.p. 52)) Ethyl 163 0.01 1.63 (started 1dichlorophosphate with 1.732 (Aldrich, Batch # dissolved in 03509AC) 10mL CH₂Cl₂) DMAP 2.67 mMol 0.0025 ~1 0.25 (Aldrich # 359882 per 1 g Lot #14121PB) (2.67 mMol per 1 g) Triethylamine 101 0.015 1.515 1.5 (Burdick& Jackson Lot # CH130)

The general reaction scheme for the synthesis of this phosphoesterfunctionalized mPEG was as follows:

After filtration, the resulting solution of phosphoester terminated mPEGwas then reacted with spermine to form an amine terminated phosphoesterfunctional mPEG. Spermine was dissolved in about 10 mL ofdimethylformamide (DMF) and triethylamine was added to act as an HClscavenger. The compounds utilized in this part of the synthesis andtheir amounts are set forth below in Table 2:

TABLE 2 Compound MW Mols Weight(g) Mol Ratio Spermine 202 0.01 2.02 1Triethylamine 101 0.015 1.515 1.5

The spermine/trimethylamine/DMF solution was added dropwise to thephosphoester functionalized mPEG at a temperature of about O° C. After aperiod of about 4 hours a precipitate was obtained. The material wassubjected to filtering and evaporation: the filtrate was a colorlessliquid. After reducing the volume about 90% through evaporation theresulting material was precipitated in PE/ether. After precipitation inether, the white solid precipitate obtained was dried on a vacuum pumpfor about one week. Fourier transform infrared (FTIR), and nuclearmagnetic resonance (NMR) analysis were used to confirm the structure ofthe final product. The general reaction scheme for the synthesis of thisbiodegradable phosphoester polyamine was as follows:

Example 2

A methoxy polyethylene glycol was functionalized with a phosphoester asgenerally described in Example 1 above.

Polyethylene glycol having a molecular weight of about 200 (PEG),triethylamine (NEt3) and dimethylaminopyridine (DMAP) were dissolved indichloromethane. The materials were combined in a flask and cooled downto about 0° C. A solution containing dichloromethane and ethyldichlorophosphate (EOP) was added dropwise under nitrogen. The reactionoccurred at a temperature of about 0° C. and was allowed to proceed forabout 2 hours. The materials were then stored overnight.

The compounds utilized in the synthesis are set forth below in Table 3:

TABLE 3 Compound MW Mols Weight(g) Mol Ratio PEG 200 200 0.02 4 1(Aldrich, Lot # 05714JF) Ethyl 163 0.04 6.52 2 dichlorophosphate(Aldrich, Batch # 03509AC) DMAP 2.67 mMol 0.005 ~2 0.25 (Aldrich #359882 per 1 g Lot # 14121PB) (2.67 mMol per 1 g) Triethylamine 101 0.066.06 3 (Burdick & Jackson Lot # CH130)

The resulting material was subjected to filtering and evaporation of thefiltrate on a ROTAVAPOR® rotary evaporator, (BÜCHl Labortechnik AG),then collected by precipitation in ether to obtain a dry whiteprecipitate. The precipitate was redissolved in about 150 mL of DMF andfiltered again.

Spermine was dissolved in about 150 mLs of DMF and triethylamine wasadded to act as a HCl scavenger. The spermine was then added to theprecipitate described above. The compounds utilized in this part of thesynthesis and their amounts are set forth below in Table 4:

TABLE 4 Compound MW Mols Weight(g) Mol Ratio Spermine 202 0.04 8.08 2Triethylamine 101 0.06 6.06 3

The DMF solution of spermine/trimethylamine was added dropwise to thephosphoester functionalized PEG-200 at a temperature of about O° C. withstirring overnight. The resulting material was collected by filteringthe salt of DMF under vacuum at about 60° C. The final product obtainedwas a viscous oil. Yield was >90% and the structure was confirmed byNMR, IR and differential scanning calorimetry (DSC).

It will be appreciated that various of the above-disclosed and otherfeatures and functions, or alternatives thereof, may be desirablycombined into many other different systems or applications. Also thatvarious presently unforeseen or unanticipated alternatives,modifications, variations or improvements therein may be subsequentlymade by those skilled in the art which are also intended to beencompassed by the following claims. Unless specifically recited in aclaim, steps or components of claims should not be implied or importedfrom the specification or any other claims as to any particular order,number, position, size, shape, angle, color, or material.

What is claimed is:
 1. A biocompatible composition comprising: abiodegradable phosphoester polyamine of the following formula:

wherein R¹ is selected from the group consisting of polyethers,polyesters, poly(ether-ester) blocks and combinations thereof, R² is ahydrogen atom, a protecting group or an organic moiety having from about1 to about 50 carbon atoms, and NH—R³—NH₂ is derived from a polyamineselected from the group consisting of ethylene diamine, hexamethylenediamine, lysine, N-(3-aminopropyl)-1,4-butanediamine,N,N′-bis(3-aminopropyl)-1,4-butanediamine, isomers of hexamethylenediamine, diethylene triamine, triethylene tetramine, tetraethylenepentamine, bishexamethylene triamine, N,N′-bis(3-aminopropyl)-1,2-ethanediamine, N-(3-Aminopropyl)-1,3-propane diamine, N-(2-aminoethyl)-1,3propane diamine, cyclohexane diamine, isomers of cyclohexane diamine,4,4′-methylene biscyclohexane amine, 4′4′-methylenebis(2-methylcyclohexanamine), toluene diamine, phenylene diamine,isophorone diamine, phenalkylene polyamines, amino-functionalizedpolyalkylene oxides, polypeptides, and combinations thereof.
 2. Thebiocompatible composition of claim 1, wherein R¹ comprises a polyetherselected from the group consisting of polyethylene glycol, methoxypolyethylene glycol, polypropylene glycol, polybutylene glycol,polytetramethylene glycol, polyhexamethylene glycol, copolymers thereof,and combinations thereof.
 3. The biocompatible composition of claim 1,wherein R¹ comprises a polyester selected from the group consisting oftrimethylene carbonate, ε-caprolactone, p-dioxanone, glycolide, lactide,1,5-dioxepan-2-one, polybutylene adipate, polyethylene adipate,polyethylene terephthalate, and combinations thereof.
 4. Thebiocompatible composition of claim 1, wherein R¹ comprises apoly(ether-ester) block selected from the group consisting ofpolyethylene glycol-polycaprolactone, polyethylene glycol-polylactide,polyethylene glycol-polyglycolide, and combinations thereof.
 5. Thebiocompatible composition of claim 1, wherein R¹ is selected from thegroup consisting of polyethylene glycol, methoxy polyethylene glycol,glycolide-polyethylene glycol-caprolactone copolymers, aliphaticoligoesters, and combinations thereof.
 6. An adhesive comprising thebiocompatible composition of claim
 1. 7. A sealant comprising thebiocompatible composition of claim
 1. 8. A biocompatible compositioncomprising: an isocyanate prepolymer; and a biodegradable phosphoesterpolyamine of the following formula:

wherein R¹ is selected from the group consisting of polyethers,polyesters, poly(ether-ester) blocks and combinations thereof, R² is ahydrogen atom, a protecting group or an organic moiety having from about1 to about 50 carbon atoms, and NH—R³—NH₂ is derived from a polyamineselected from the group consisting of ethylene diamine, hexamethylenediamine, lysine, N-(3-aminopropyl)-1,4-butanediamine,N,N′-bis(3-aminopropyl)-1,4-butanediamine, isomers of hexamethylenediamine, diethylene triamine, triethylene tetramine, tetraethylenepentamine, bishexamethylene triamine, N,N′-bis(3-aminopropyl)-1,2-ethanediamine, N-(3-Aminopropyl)-1,3-propane diamine, N-(2-aminoethyl)-1,3propane diamine, cyclohexane diamine, isomers of cyclohexane diamine,4,4′-methylene biscyclohexane amine, 4′4′-methylenebis(2-methylcyclohexanamine), toluene diamine, phenylene diamine,isophorone diamine, phenalkylene polyamines, amino-functionalizedpolyalkylene oxides, polypeptides, and combinations thereof, wherein thebiodegradable phosphoester polyamine crosslinks the isocyanateprepolymer.
 9. The biocompatible composition of claim 8, wherein theisocyanate prepolymer is of the formula

wherein X is selected from the group consisting of polyethers,polyesters and polyether-esters, and R is selected from the groupconsisting of aromatic groups, aliphatic groups, and alicyclic groups.10. A method for adhering tissue comprising: approximating a firsttissue surface and a second tissue surface; and applying thebiocompatible composition of claim 8 to the approximated first andsecond tissue surfaces to adhere the first tissue surface to the asecond tissue surface.
 11. A method for adhering a medical device to atissue surface, the method comprising: approximating a medical deviceand a tissue surface; and applying the biocompatible composition ofclaim 8 to the medical device, to the tissue surface, or both, whereinapplying the biocompatible composition adheres the medical device to thetissue surface.